Sodium Valproate

SCOPE — INTRAVENOUS EPILEPSY DOSING ONLY, from the UK SPC for the 100 mg/ml solution for injection or infusion. Oral sodium valproate dosing is not covered by this bundle. §4.2 verbatim: 'Daily dosage requirements vary according to age and body weight. Each vial of Sodium valproate injection is for single dose injection only. Adults Patients already satisfactorily treated with oral sodium valproate may be continued at their current dosage using continuous or repeated infusion. Other patients may be given a slow intravenous injection over 3 – 5 minutes, usually 400 – 800 mg depending on body weight (up to 10 mg/kg) followed by continuous or repeated infusion up to a maximum of 2500 mg/day. Sodium valproate injection should be replaced by oral sodium valproate therapy as soon as practicable.' || No status-epilepticus loading regimen appears anywhere in this SPC — the 40 mg/kg loading dose commonly quoted for status epilepticus is NOT in this source and is not published here. || SWITCHING FROM OTHER ANTICONVULSANTS, §4.2: 'When starting Sodium valproate injection in patients already on other anti-convulsants, these should be tapered slowly; initiation of Sodium valproate injection therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases, it may be necessary to raise the dose by 5 – 10 mg/kg/day when used in combination with anti-convulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose... When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.' || ELDERLY, §4.2: 'Although the pharmacokinetics of valproate are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.' || PLASMA LEVELS, §4.2: 'Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected.' || VALPROATE PREGNANCY PREVENTION PROGRAMME, §4.2 verbatim: 'Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated. Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme. The benefits and risks should be carefully reconsidered at regular treatment reviews. Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses.' || WITHDRAWAL, §4.4: 'discontinuation should normally only be done under the supervision of a specialist in a gradual manner'; 'NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.' || US CROSS-CHECK, NOT USED ABOVE — the openFDA label in this bundle is valproic acid ORAL solution and gives, for complex partial seizures in adults and children 10 years and older and for simple and complex absence seizures: 'Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.' and 'The maximum recommended dosage is 60 mg/kg/day.' and 'Safety of doses above 60 mg/kg/day is not established' and 'If the total daily dose exceeds 250 mg, it should be given in divided doses.' Those are US figures for a different salt and a different route and must not be applied to the intravenous UK product.

dosePerKg 20 is the LOWER BOUND of the SPC's stated usual daily requirement, entered as a starting figure; the unit is mg/kg/day because this is a TOTAL DAILY dose, not a per-dose amount. §4.2 Paediatric population verbatim: 'Daily requirement for children is usually in the range 20 – 30 mg/kg/day and method of administration is as above. Where adequate control is not achieved within this range the dose may be increased up to 40 mg/kg/day but only in patients in whom plasma valproic acid levels can be monitored. In children requiring doses higher than 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.' Always work from the full 20–30 mg/kg/day range, not from the single calculated figure. || maxDose is null because the SPC gives no absolute milligram ceiling for children — its upper limits are expressed per kilogram, and the adult 2500 mg/day ceiling is an adult figure that must not be transplanted. || §4.2 also states 'The daily dose should be divided into at least two single doses' in the Valproate Pregnancy Prevention Programme paragraph. || HEPATOTOXICITY IN THE YOUNG, §4.4.1: 'patients most at risk, especially in cases of multiple anti-convulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic disorders including mitochondrial disorders such as carnitine deficiency, urea cycle disorders, POLG mutations or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.' 'Monotherapy is recommended in children under the age of 3 years when prescribing valproate, but the potential benefit of valproate should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy.' 'The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity'; 'salicylates should not be used in children under 16 years of age (see aspirin/salicylate product information on Reye's syndrome).' || §4.3 contraindicates valproate in 'children under two years of age who are suspected of having a POLG-related disorder'. || concentration 100 is the labelled strength of the product this dosing comes from: 'Sodium Valproate 100mg/ml Solution for Injection or Infusion'. || Verify against a children's formulary before use.